title: High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins.
abstract: Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6's oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7's induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Myeong-Kyun
authors.initials: MK
authors.lastname: Shin
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000821:virology*; D006657:Histones / Q000378:metabolism; D015994:Incidence; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014059:Tongue / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C068651:E6 protein, Human papillomavirus type 16; D052236:Fanconi Anemia Complementation Group D2 Protein; D006657:Histones; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C475961:gamma-H2AX protein, mouse; C059731:oncogene protein E7, Human papillomavirus type 16